Vaso-occlusion (VOC) and its clinical manifestation, pain, are the hallmarks of sickle cell disease (SCD) and are the main causes of hospitalization and both short- and long-term disability in patients with SCD. Adhesion of red cells containing primarily hemoglobin S (SS RBCs) plays a major role in the vaso-occlusive process, but no anti-adhesive therapy for SCD is yet available or in clinical trial. We have described how SS RBC adhesion results from activation of RBC adhesion receptors via the 22-adrenergic receptor, a response not seen in normal RBCs. Physiologic concentrations of epinephrine increase adhesion of SS RBCs as well as their ability to stimulate leukocyte adhesion, which then leads to cytokine production and stimulation of pro-adhesive molecules by endothelial cells. We have recently further shown that propranolol inhibits epinephrine- induced SS RBC adhesion both in vitro and in vivo in an animal model. Moreover, we recently demonstrated that a single dose of propranolol given to SCD patients reduces RBC adhesion measured in vitro, without significant changes of blood pressure and heart rate from baseline. This discovery makes possible an entirely novel approach to SCD treatment-the use of an already FDA- approved drug, propranolol, as the first anti-adhesive therapy for SCD. We therefore propose to study the efficacy of chronic propranolol therapy in reducing SS RBC adhesion to vascular endothelium. Study Objectives: Perform a phase II propranolol vs placebo crossover study to evaluate whether chronic propranolol therapy can safely reduce the adhesion of SS RBCs to endothelial cells and thereby improve markers of endothelial cell activation and dysfunction. Methods: Up to 40 patients recruited from the Duke Sickle Cell Center will complete this study over 2 years. Subjects will be treated with a 40 mg twice daily dose of propranolol or placebo for a total of 6 weeks and then be switched to the other therapy. Patient clinical and medical histories will be obtained. Laboratory tests and EKG will be performed at baseline and periodically during the drug treatment period and after a 2-week washout period. In vitro adhesion studies and measurement of biomarkers will be performed at baseline, during the 6 weeks of treatment and at the end of the washout period to evaluate the effect of propranolol on SS RBC adhesion and endothelial dysfunction. Summary: Overall, a combination of clinical and laboratory parameters will be used to measure the efficacy of chronic propranolol therapy in reducing SS RBC adhesion, with the long term goal of gathering data sufficient to support the development of a large scale, randomized, multicenter study to determine the efficacy of propranolol in reducing the frequency of vaso-occlusion in SCD. PUBLIC HEALTH RELEVANCE: Development of therapies to treat or prevent vaso-occlusion in sickle cell disease is paramount to reducing the disease's morbidity and mortality. Our preliminary data suggest that propranolol, an inexpensive and widely available drug, might be safe and useful for this purpose. Thus, we propose to test this hypothesis in a Phase II single center clinical study.